This invention relates generally to polymer particles and methods of making and using the same.
Small (micron- and nano-sized) polymer particles are useful for many applications, including pharmaceutical uses. Polymer microparticles are useful for injectable and implantable devices because they have a long circulation time in the body and are efficient drug, enzyme, and protein carriers (Tom, J. W. et al. (1993), xe2x80x9cApplications of Supercritical Fluids in the Controlled Release of Drugs,xe2x80x9d in Supercritical Fluid Engineering Science, pp. 238-257). Crosslinked polymer microparticles have material property benefits over linear polymer particles including improved mechanical strength, greater control of transport properties, material property adjustability and dimensional stability. Some applications of cross-linked polymers are listed in Cooper, A. L. and Holmes, A. B. (1998) Proceedings of the 5th Meeting of Supercritical Fluids Materials and Natural Products Processing, pp. 843-848. Polymer microparticles (both linear and crosslinked) have been used in applications such as dental composites, biostructural fillers and controlled release devices. Some applications of synthetic bone composites are listed in Popov, V. K. et al. (1998) Proceedings of the 5th Meeting of Supercritical Fluids Materials and Natural Products Processing, pp. 45-50.
Controlled release devices are useful in many applications, from medical to agricultural (Langer, R. (1993), Polymer-Controlled Drug Delivery Systems,xe2x80x9d Acc. Chem. Res. 26:537-542; U.S. Pat. No. 5,043,280). Controlled release delivery systems for drugs have at a wide variety of advantages over conventional forms of drug administration. Some of these advantages include: decreasing or eliminating the oscillating drug concentrations found with multiple drug administrations; allowing the possibility of localized delivery of the drug to a desired part of the body; preserving the efficacy of fragile drugs; reducing the need for patient follow-up care; increasing patient comfort and improving patient compliance. (Langer, R. (1990), xe2x80x9cNew Methods of Drug Delivery,xe2x80x9d Science 249:1527-1533).
Current polymer microparticle manufacturing techniques all suffer from one or more disadvantages. For example, the spray drying technique usually requires evaporation of solvent in hot air. The high temperatures used can degrade sensitive drugs and polymers. In thermal polymerization, monomer is heated to induce polymerization. Again, the high temperatures used can cause degradation (including lowering the activity of biologically active substances).
Emulsion and suspension polymerizations (see, for example, U.S. Pat. No. 5,603,960 (O""Hagan., et al.)) involve combinations of solvents, emulsifiers, and surfactants where dispersed islands of monomer polymerize through chemical reaction in a sea of solvent. These methods often involve operation at high temperatures and thus have the problems discussed above, use large volumes of solutions that are often environmentally unfriendly, and permit only minimal control over particle size and morphology.
A number of different techniques have been developed to form small particles of polymers using the solvent power of supercritical fluids. Supercritical fluids have liquid-like densities, very large compressibilities, viscosities between those of liquids and gases, and diffusion coefficients that are higher than liquids. Due to the high compressibility, the density (and solvent power) of a supercritical fluid can be adjusted between gas- and liquid-like extremes with moderate changes in pressure (Debenedetti, P. G. et al. (1993), xe2x80x9cRapid Expansion of Supercritical Solutions (RESS): Fundamentals and Applications,xe2x80x9d Fluid Phase Equilibria 82:311-321).
The Rapid Expansion of Supercritical Solution (RESS) technique has been used to form small particles of poly(L-lactic acid) (Debenedetti, P. G. et al. (1993), xe2x80x9cSupercritical Fluids: A New Medium for the Formation of Particles of Biomedical Interest,xe2x80x9d Proceed. Interm. Symp. Control Rel. Bioact. Mater. 20:141-142) and particles of poly(DL-lactic acid) with embedded lovastatin (Tom, J. W. et al. (1993), xe2x80x9cApplications of Supercritical Fluids in the Controlled Release of Drugs,xe2x80x9d in Supercritical Fluid Engineering Science, pp. 238-257). In the RESS technique, particles of polymer may be made when a polymer is dissolved in a supercritical fluid (usually carbon dioxide) followed by rapid expansion of the fluid. This technique is limited in applicability to compounds that are soluble in the supercrifical fluid. Since most drugs are not soluble in supercritical fluids and most polymers have very low solubility in supercritical fluids, the RESS process is not broadly applicable for drug encapsulation (McHugh, M. and Krukonis, V. (1994) Supercritical Fluid Extraction, Butterworth-Heinemann).
In the Precipitation by a Compressed Antisolvent (PCA) technique (also known as the Gas Antisolvent technique), a solid of interest is dissolved in a solvent and the resulting solution is sprayed into a compressed antisolvent (see, for example, U.S. Pat. Nos. 5,833,891 and 5,874,029). In this technique, the antisolvent and solvent are soluble, but the solid of interest is not soluble in the antisolvent. The antisolvent is believed to extract the solvent, precipitating particles of the solid of interest (Randolph, T. W. et al. (1993)Biotech. Prog. 9:429-435). Microparticles of insulin have reportedly been formed using this technique (Yeo, S.-D. et al. (1993), xe2x80x9cFormation of Microparticulate Protein Powders Using a Supercritical Fluid Antisolvent,xe2x80x9d Biotech. Bioeng. 41:341-346) and polymer microparticles have been formed using polymer starting materials (Bodmeier, R. et al. (1995), xe2x80x9cPolymeric Microspheres Prepared by Spraying into Compressed Carbon Dioxide,xe2x80x9d Pharm. Res. 12(8):1211-1217; U.S. Pat. Nos. 5,833,891; 5,874,029).
There is a need for polymer particles with low residual solvent levels, high additive encapsulation efficiencies, and processes of making polymer particles that allow control of particle size and morphology, with low operating temperatures and efficient bulk production capability. Formation of polymer particles with erodable surfaces are also needed for controlled release of drugs, for example. In particular, highly crosslinked polymer networks with erodable surfaces are desired. In addition, there is a need for a process that produces polymer particles in situ from polymer precursors such as monomers or oligomers.
In a general description of the invention, a method of forming polymer particles comprising exposing a composition comprising at least one polymer precursor, a solvent or solvent mixture, and an antisolvent or antisolvent mixture to photoradiation under conditions whereby particles are formed is provided. If the precursor is not photosensitive, at least one photoinitiator is present in the composition. The solvent is not required if the polymer Sri precursor is liquid or liquifiable. If used, the solvent is chosen so that the polymer precursor is soluble in the solvent at the concentrations used, and the antisolvent and solvent are soluble in each other at the concentrations used. The polymer precursor is preferably insoluble in the antisolvent, but as long as nucleation and particle formation occur, any solubility condition may be present. Bioactive materials such as drugs may also be included in the composition.
Also provided is a method of forming polymer particles comprising contacting a solution comprising a solvent or solvent mixture and at least one polymer precursor with an antisolvent or antisolvent mixture under conditions whereby particles are generated; and exposing said particles to photoradiation, whereby polymer particles are formed. Preferably the polymer precursor is insoluble in the antisolvent or antisolvent mixture.
Also provided are polymer particles prepared by the methods of the invention that are between about 0.001 xcexcm to about 100 xcexcm in diameter. Linear and crosslinked polymer particles may be formed using the methods of the invention.
Also provided is a method of forming polymer particles comprising: substantially dissolving at least one polymer precursor in a solvent or solvent mixture to form a solution; contacting said solution with an antisolvent or antisolvent mixture in which said polymer precursor is insoluble to form a composition comprising said precursor, and a substantially soluble mixture of said solvent or solvent mixture and said antisolvent or antisolvent mixture; and exposing said composition to sufficient photoradiation to initiate polymerization whereby polymer particles are formed.
Also provided is a method of forming polymer particles comprising: establishing a flow of antisolvent in an optically accessible chamber; contacting a solution comprising at least one polymer precursor and at least one polymerization initiator dissolved in a solvent or solvent mixture with said antisolvent under conditions whereby particles are formed; and exposing said particles to photoradiation whereby polymer particles are formed.
Also provided is a method of forming copolymers comprising: dissolving or suspending at least two polymer precursors or at least one polymer precursor and at least one polymer in a solvent or solvent mixture to form a solution; contacting said solution with an antisolvent or antisolvent mixture to form a composition comprising: said precursors or said precursor and polymer; a soluble mixture of said solvent or solvent mixture and said antisolvent or antisolvent mixture; and exposing said composition to photoradiation whereby copolymer particles are formed.
Copolymers may also be formed where at least one polymer precursor or at least one polymer are present in a solvent or solvent mixture, and at least one polymer precursor or at least one polymer are present in the antisolvent or antisolvent mixture, providing that at least one polymer precursor is present.
Also provided is a method of forming particles comprising a bioactive material and a polymer comprising: exposing a composition comprising at least one bioactive material, at least one polymer precursor and an antisolvent or antisolvent mixture to photoradiation under conditions whereby particles are formed.
Polymers formed may be erodable or nonerodable, biodegradable or nonbiodegradable and biocompatible or nonbiocompatible. Polymer particles formed using the methods of the invention may be used for controlled release of a desired substance in an organism or system. Provided is a method of controlled release of a desired substance comprising: preparing polymer particles that comprise a degradable polymer and a desired substance; and exposing said polymer particles to conditions under which the polymer is degraded.
Methods of forming degradable particles comprising a degradable polymer and a pharmaceutical product comprising: exposing a composition comprising a solvent or solvent mixture, at least one polymer precursor capable of forming a degradable polymer, at least one pharmaceutical product, and an antisolvent or antisolvent mixture to photoradiation whereby polymer particles that contain a degradable polymer and a pharmaceutical product are formed are provided.
A pharmaceutical composition comprising polymer particles produced by the methods of the invention and a pharmaceutically acceptable carrier are also provided. Polymer particles comprising at least one bioactive material and at least one polymer are also provided.
Crosslinked polymer particles comprising a degradable polymer are also provided. Crosslinked polymer particles comprising a polyanhydride are provided. Biodegradable crosslinked polymer particles are also provided. Crosslinked polymer particles further comprising at least one bioactive material are also provided.
An apparatus is provided for producing polymer microparticles which comprises: a reaction chamber; at least one inlet into said reaction chamber through which an antisolvent or antisolvent mixture, at least one polymer precursor insoluble in said antisolvent or antisolvent mixture, and a solvent or solvent mixture soluble in said antisolvent or antisolvent mixture pass into said chamber; and a light source optically connected to said chamber wherein during operation of the chamber said polymer precursor is polymerized. The apparatus may be used with a photosensitive polymer precursor, or a polymerization initiator may be added.
Advantages of this photopolymerization technique include morphological control through polymerization rate, process conditions, and initiation location. Processing time remains short while processing temperatures remain low. Low operating temperatures are important since many potential encapsulation additives degrade at moderate temperatures. In addition, particles formed using the method of the invention do not require further processing, for example solvent removal, before use.
Further objects and advantages of this invention will be apparent from a consideration of the drawings and description herein.
xe2x80x9cMicroparticlesxe2x80x9d as used herein means particles that are less than about 100 xcexcm in diameter. xe2x80x9cNanoparticlesxe2x80x9d are particles that are less than about 1 xcexcm in diameter. Both microparticles, nanoparticles and particles of other sizes may be produced by the methods of the invention by changing process parameters and choice of materials. Methods of changing the process parameters and materials are described herein, or determinable by one of ordinary skill in the art without undue experimentation.
xe2x80x9cPolymer precursorxe2x80x9d means a molecule or portion thereof which can be polymerized to form a polymer or copolymer. Polymer precursors include any substance that contains an unsaturated moiety or other functionality that can be used in chain polymerization, or other moiety that may be polymerized in other ways. Such precursors include monomers and oligomers. Preferred precursors include those that are capable of being polymerized by photoradiation. One class of polymer precursors of the invention are those that are insoluble in the antisolvent or antisolvent mixture. Another class of polymer precursors of this invention are photosensitive. If a polymer precursor that polymerizes photochemically is used (photosensitive polymer precursor), a separate photoinitator does not need to be used. Examples of photosensitive polymer precursors include tetramercaptopropionate and 3,6,9,12-tetraoxatetradeca-1,13-diene. Another class of precursors that may be used are radically polymerizable precursors. Another class of precursors that may be used are ionically polymerizable precursors. Another class of precursors that are useful in the invention are cationic precursors.
Some examples of precursors that are useful in the invention include ethylene oxides (for example, PEO), ethylene glycols (for example, PEG), vinyl alcohols (for example, PVA), vinyl pyrrolidones (for example, PVP), ethyloxazolines (for example, PEOX), amino acids, saccharides, proteins, anhydrides, vinyl ethers, amides, carbonates, phenylene oxides (for example, PPO), acetals, sulfones, phenylene sulfides (for example, PPS), esters, fluoropolymers, imides, amide-imides, etherimides, ionomers, aryletherketones, olefins, styrenes, vinyl chlorides, ethylenes, acrylates, methacrylates, amines, phenols, acids, nitriles, acrylamides, maleates, benzenes, epoxies, cinnamates, azoles, silanes, chlorides, epoxides, lactones and amides.
As used herein, xe2x80x9cpolymerxe2x80x9d includes copolymers. xe2x80x9cCopolymersxe2x80x9d are polymers formed of more than one polymer precursor. Polymers that can be formed using the methods of this invention include those which are prepared from precursors that, in a preferred embodiment are soluble in a solvent that is soluble in an antisolvent and can be polymerized with light initiation. One class of polymers that may be prepared using the method of this invention include those that are degradable, preferably biodegradable. Another class of polymers that may be prepared using the method of this invention include those that are not degradable. Another class of polymers that may be prepared using the method of this invention include those that comprise one or more degradable polymers and one or more nondegradable polymers. Another class of polymers that may be prepared using the method of this invention include poly lactic acids. In a preferred embodiment of the invention, the polymers are degradable or erodable.
xe2x80x9cDegradable or erodable polymersxe2x80x9d are those that degrade upon exposure to some stimulus, including time. Degradable or erodable polymers include biodegradable polymers. Biodegradable polymers degrade in a biological system, or under conditions present in a biological system. Preferred biodegradable polymers degrade in an organism, preferably a mammal, and most preferably human. Examples of biodegradable polymers include those having at least some repeating units representative of at least one of the following: an alpha-hydroxycarboxylic acid, a cyclic diester of an alpha-hydroxycarboxylic acid, a dioxanone, a lactone, a cyclic carbonate, a cyclic oxalate, an epoxide, a glycol, and anhydrides. Preferred degradable or erodable polymers comprise at least some repeating units representative of polymerizing at least one of lactic acid, glycolic acid, lactide, glycolide, ethylene oxide and ethylene glycol.
A class of polymers included in this invention are biocompatible polymers. One type of biocompatible polymers degrade to nontoxic products. Specific examples of biocompatible polymers that degrade to nontoxic products that do not need removal from biological systems include poly(hydro acids), poly (L-lactic acid), poly (D,L-lactic acid), poly (glycolic acid) and copolymers thereof. Polyanhydrides have a history of biocompatibility and surface degradation characteristics (Langer, R. (1993) Acc. Chem. Res. 26:537-542; Brem, H. et al. (1995) Lancet 345:1008-1012; Tamada, J. and Langer, R. J. (1992) J. Biomat Sci.-Polym. Ed. 3:315-353).
Another class of polymers that may be prepared using the method of this invention include particles that are a suitable size for injection or administration orally or incorporated in a preparation suitable for oral administration. For oral or injectable delivery, it is preferred that most particles are less than 50 microns in diameter. Another class of particles that may be prepared using the method of this invention include those that are a suitable size for inhalation or pulmonary delivery. For pulmonary delivery, it is preferred that greater than about 90 weight percent of all solid particles in an administered pharmaceutical formulation are of a size smaller than about 10 microns and more preferably at least about 90 weight percent are smaller than about 6 microns, and even more preferably at least about 90 percent of all solid particles are from about 1 micron to about 6 microns. Particularly preferred for pulmonary delivery applications are particles of from about 2 microns to about 5 microns in size. Other classes of particles of suitable size for various applications are included in the methods of the invention.
Solvents useful in the invention include those that dissolve some portion of a polymer precursor and are preferably at least partially soluble in the antisolvent used. Preferably the solvent is miscible in the antisolvent or antisolvent mixture at the temperature and pressure of operation. Preferred solvents are not water. Some examples of preferred solvents include methylene chloride, methanol, toluene, propanol, ethanol, acetone, ethers, hexanes and heptane. If a liquid or liquidizable polymer precursor is used, a solvent is not necessary. One solvent or a mixture of solvents may be used.
Photoinitiators that are useful in the invention include those that can be activated with light and initiate polymerization of the polymer precursor. Preferred initiators include azobisisobutyronitrile, peroxides, phenones, ethers, quinones, acids, formates. Cationic initiators are also useful in the invention. Preferred cationic initiators include aryldiazonium, diaryliodonium, and triarylsulfonium salts. Most preferred initiators include Rose Bengal (Aldrich), DAROCUR 2959 (2-hydroxy-1-[4-(hydroxyethoxy)phenyl]-2-methyl-1-propanone, D2959, Ciba-Geigy), IRGACURE 651 (2,2dimethoxy-2-phenylacetophenone, 1651, DMPA, Ciba-Geigy), IRGACURE 184 (1-hydroxycyclohexyl phenyl ketone, 1184, Ciba-Geigy), IRGACURE 907 (2-methyl-1-[4-(methylthio)phenyl]-2-(4-morpholinyl)-1-propanone, 1907, Ciba-Geigy), camphorquinone (CQ, Aldrich), isopropyl thioxanthone (QUANTACURE ITX, Great Lakes Fine Chemicals LTD., Cheshire, England). CQ is typically used in conjunction with an amine such as ethyl 4-N,N-dimethylaminobenzoate (4EDMAB, Aldrich) or triethanolamine (TEA, Aldrich) to initiate polymerization.
The wavelengths and power of light useful to initiate polymerization depends on the initiator used or the wavelength (or wavelengths) will activate the photosensitive precursor. A combination of photosensitive precursor(s) and photoinitiator(s) may be used. When Rose Bengal is used as the initiator, a visible light source is preferably used. Light used in the invention includes any wavelength and power capable of initiating polymerization. Preferred wavelengths of light include ultraviolet or visible. Any suitable source may be used, including laser sources. The source may be broadband or narrowband, or a combination.
Chamber windows made from various materials may be used in the method of this invention. In addition, a filter may used to block a wavelength from reaching the chamber, or allow a selected wavelength or wavelengths of light to reach the chamber. The chamber windows themselves may act as this filter, or a separate filter or filters may be used in conjunction with the chamber windows.
In one embodiment, a broadband light source may be used, and by selecting chamber window compositions and/or filter combinations, the selected wavelength or wavelengths of light may pass through the chamber. Light of different selected wavelengths may pass through the same chamber at various locations. This feature may be used to activate more than one photoinitiator.
As used herein, xe2x80x9cantisolventxe2x80x9d is a substance in which the polymer precursor is substantially not soluble. It should be understood that it is possible that the antisolvent may be capable of dissolving some amount of the precursor without departing from the scope of the present invention. The antisolvent is, however, preferably incapable of dissolving a significant portion of the precursor such that at least a significant portion of precursor is, in effect, not soluble in the antisolvent. Preferably, the antisolvent precipitation is conducted under thermodynamic conditions which are near critical or supercritical relative to the antisolvent fluid. The antisolvent preferably comprises any suitable fluid for near critical or supercritical processing. These fluids include carbon dioxide, ammonia, nitrous oxide, methane, ethane, ethylene, propane, butane, pentane, benzene, methanol, ethanol, isopropanol, isobutanol, fluorocarbons (including chlorotrifluoromethane, monofluoromethane, hexafluoraethane and 1,1-difluoroethylene), toluene, pyridine, cyclohexane, m-cresol, decalin, cyclohexanol, o-xylene, tetralin, aniline, acetylene, chlorotrifluorosilane, xenon, sulfur hexafluoride, propane and others. Carbon dioxide, ethane and propane are preferred antisolvents. Most preferably, carbon dioxide is used as the antisolvent. One antisolvent, or a mixture of different antisolvents may be used.
As used herein, xe2x80x9csupercritical or near supercritical fluidxe2x80x9d means a substance that is above its critical pressure and temperature or is substantially near its critical pressure and temperature.
Components that are xe2x80x9ccontactedxe2x80x9d with each other refers to two or more components physically near each other. Components that are contacted with each other are preferably in intimate contact with each other so that they may react with each other or affect each other.
A xe2x80x9cbioactivexe2x80x9d material is any substance which may be administered to any biological system, such as an organism, preferably a human or animal host, and causes some biological reaction. Bioactive materials include pharmaceutical substances, where the substance is administered normally for a curative or therapeutic purpose. The bioactive material may comprise a protein or other polypeptide, an analgesic or another material.
A xe2x80x9cpolymer shellxe2x80x9d may be a continuous coating of polymer over some substance, but the coating is not required to be continuous. The polymer shell may have nonhomogeneous I, regions where there is no coating, or regions where the coating is thicker than in other areas. The polymer shell may be composed of different materials. Preferably, the polymer shell is a homogeneous coating with uniform thickness. xe2x80x9cEncapsulatedxe2x80x9d is intended to indicate a substance, such as a bioactive material, is homogeneously distributed throughout the polymer.
xe2x80x9cLinear polymersxe2x80x9d are those polymers that are composed of individual polymer chains that do not have bonds connecting the chains. xe2x80x9cCrosslinked polymersxe2x80x9d are those polymers that have bonds between polymer chains. Branched polymers are also included in the invention.
xe2x80x9cSolublexe2x80x9d does not necessarily mean completely soluble. As long as some portion of one substance dissolves in another substance, the substances are soluble in each other. Likewise, xe2x80x9cinsolublexe2x80x9d does not necessarily mean that no amount of one substance will dissolve in another substance.
A xe2x80x9ccompositionxe2x80x9d of substances is not intended to mean the substances are soluble or miscible with each other, or react with each other. A xe2x80x9ccompositionxe2x80x9d is merely intended to mean all listed substances are present.